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Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I

Lookup NU author(s): Ahmad Alahmad, Dr Kyle Thompson, Dr Monika Olahova, Dr Langping He, Dr Charlotte Alston, Professor Bobby McFarlandORCiD, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2020 The Authors. Published under the terms of the CC BY 4.0 licenseLeigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects’ fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects’ fibroblasts with wild-type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module.

Publication metadata

Author(s): Alahmad A, Nasca A, Heidler J, Thompson K, Olahova M, Legati A, Lamantea E, Meisterknecht J, Spagnolo M, He L, Alameer S, Hakami F, Almehdar A, Ardissone A, Alston CL, McFarland R, Wittig I, Ghezzi D, Taylor RW

Publication type: Article

Publication status: Published

Journal: EMBO Molecular Medicine

Year: 2020

Volume: 12

Issue: 11

Online publication date: 06/11/2020

Acceptance date: 26/08/2020

Date deposited: 08/01/2021

ISSN (print): 1757-4676

ISSN (electronic): 1757-4684

Publisher: Blackwell Publishing Ltd

URL: https://doi.org/10.15252/emmm.202012619

DOI: 10.15252/emmm.202012619

PubMed id: 32969598

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